Profile of Daniel A. Haber PROFILE

PROFILE Profile of Daniel A. Haber PROFILE Beth Azar, Science Writer Research oncologist Daniel Haber may not have changed when he enrolled in treated patients in years, but they are never far from the English program at the his mind. “When I started my MD/PhD program at International School of Ge- Stanford I thought I could be both a physician and a neva, where he excelled researcher,” says Haber, director of the Massachusetts in science. General Hospital (MGH) Cancer Center, where he also For college, Haber decided runs a cancer research laboratory. “But at some point to explore his American roots the research became dominant in terms of my interest andappliedtotheMas- and my ability. I tried to make up for it by directing my sachusetts Institute of Tech- research toward very clinically relevant questions.” nology, thinking he would Haber’s research focuses on using human genetics study biomedical engineering. to tackle cancer through early diagnosis and targeted Once there, he realized he treatments. He was among the first to find targetable preferred biology and medi- genetic mutations that cause cancer, discovering a cine, so, as a sophomore Haber mutation in lung cancer that helped lay the foundation began volunteering in William for widespread testing of cancers with treatable muta- Thilly’s cancer biology labora- tions. He is also making strides in detecting rare can- tory. He completed his un- cer cells circulating in blood, with the goal of early dergraduate degree in life detection and treatment. Haber’s Inaugural Article sciences in 3 years and spent (1) identifies a signaling pathway that switches on dor- his fourth year working in the mant metastatic tumor cells that have spread through laboratory, earning a Master’s Daniel A. Haber. Image courtesy of Mark blood. This work could lead to ways to prevent cancer degree in genetic toxicology Karlsberg (Studio Eleven, Newton, MA). from spreading through blood. in 1977. Haber is the Kurt J. Isselbacher Professor of Unable to decide between Oncology at Harvard Medical School and has been a being a physician and a researcher, Haber set his Howard Hughes Medical Institute investigator since sights on a medical degree and Doctorate of Philos- 2008. He was elected to the National Academy of ophy, and applied to Stanford University. “It was an Sciences in 2018. exciting new time and the science there was really unequalled,” recalls Haber. At Stanford, he worked in Finding His Mission the laboratory of biochemist Robert Schimke, a pio- Haber’s father taught him the importance of helping neer in developing ways to clone DNA. Just before people. The elder Haber worked for an organization Haber arrived, Schimke’s graduate student, Fred Alt, founded in 1881 to assist Jews fleeing pogroms and discovered that cancer cells can amplify their DNA as that today resettles refugees in the United States. “He they become resistant to chemotherapy drugs. had a sense of mission,” Haber says of his father. “He “The assumption had been that DNA was stable wanted his life to be about doing something that was and no cell could change its DNA,” says Haber. “Fred larger than himself, something meaningful. That was discovered that as the chemotherapy drug metho- inspiring to me.” Haber’s mother had a successful trexate blocks its target enzyme, called DHFR, the cell career in financial investing. Haber and his sister were becomes resistant by amplifying the number of DHFR raised in Paris until they moved to Geneva, Switzer- gene copies until there are hundreds of DHFR genes land when Haber was 5 years old. The family spoke making massive amounts of proteins to overcome the French at home, although Haber’s mother spoke drug inhibition.” French and English with an equally terrible Hungarian Haber was fascinated by the idea that the genome accent, quips Haber. By the time Haber reached high could be so plastic and decided to study the process school, his English was broken at best. That quickly of gene amplification. For his graduate thesis, Haber Published under the PNAS license. This is a Profile of a member of the National Academy of Sciences to accompany the member’s Inaugural Article, 10.1073/pnas.1819303116. www.pnas.org/cgi/doi/10.1073/pnas.1903223116 PNAS Latest Articles | 1of3 Downloaded by guest on September 25, 2021 discovered a mutant DHFR enzyme with altered what are you going to be really good at. That’s when I binding to methotrexate (2). With that work, Haber decided to step back from my clinical responsibilities.” was hooked on cancer research. Shaping Cancer Research and Treatment Stepping Away from the Clinic When Isselbacher stepped down from directing the Haber had found his research passion, but he still had cancer center in 2003, Haber was recruited to take his to finish medical school. He landed an internship and place. Meanwhile, his research team has helped shape residency at MGH and an oncology fellowship at Dana MGH’s approach to cancer treatment by pushing the Farber Cancer Institute. After 4 years of clinical work, idea of mutation-driven therapies. Haber returned to research as a postdoctorate in Haber’s most important discovery was inspired by David Housman’s cancer research laboratory at the a profile in The Boston Globe. A woman with lung Massachusetts Institute of Technology. He wanted to cancer had been treated at MGH with an experimental expand his earlier research studying cancer genetics. drug and her tumor appeared to melt away. The same “The work that David was doing discovering new drug was ineffective for most patients with lung can- human disease genes through positional cloning re- cer. The drug targeted a growth factor called EGFR, ally excited me,” says Haber. “And he was a wonderful which is expressed by almost all cancers, so Haber person and mentor, very inspiring for me.” wondered whether tumors that responded to the drug Haber’s research (3) helped identify the gene WT1, might have a mutation in the EGFR gene. His labora- which causes the childhood kidney cancer, Wilms tu- tory tested tumor samples from nine people who had mor. Haber’s main goal was to test the “Knudson hy- dramatic responses to the drug; eight of those cases pothesis,” which postulates that inherited cancers had EGFR gene mutations. There were no mutations occur only if both alleles of a tumor-suppressor gene in any of seven nonresponding tumors (6). This dis- have a mutation and that, in familial cases, earlier and covery, along with a paper from another laboratory multiple cancers arise because a mutant allele is group (7), not only transformed the treatment of lung transmitted in the germline. His research supported cancer but also helped launch national efforts to test tumors for rare mutations at the time of diagnosis, the hypothesis. The WT1 gene has now emerged as a setting the stage for genetically targeted precision major immunogenic target in leukemia vaccine therapy oncology. trials. “We learned that 10% of lung cancers have EGFR Haber moved to MGH in 1989 to work in its newly mutations, and this is the single oncogenic driver in created cancer center. “I was the seventh faculty most cancers that arise in nonsmokers,” says Haber. member hired,” says Haber, who was recruited by Kurt “The tumor is ‘addicted’ to the mutant EGFR onco- Isselbacher, the center’s first director. “It was a phe- gene, and depends on it for growth.” nomenal atmosphere in which to conduct research.” However, targeted drugs are only effective until There, he continued working on Wilms tumor biology, cancer cells develop new mutations that make them eventually cloning a second Wilms tumor-suppressor resistant. The trick, says Haber, is to catch the cancers gene, WTX, located on the X chromosome (4). earlier, when there may be fewer resistant cancer cells, Meanwhile, researchers had cloned another tumor- and the treatments have a chance to be curative. suppressor gene in breast cancer, BRCA1. Haber’s Hence, Haber recently turned his research toward colleague Stephen Friend had collected blood sam- early cancer detection. ples from 400 women who had developed breast With his bioengineering colleague Mehmet Toner ’ cancer before age 40. Haber s team tested these and his collaborator Shyamala Maheswaran, Haber samples for germline mutations and discovered that developed and tested microfluidic devices to find rare 10% of the women had a BRCA gene mutation, irre- circulating tumor cells (CTCs) that invasive cancers spective of their family history. In addition, a single shed into the bloodstream, long before they establish “ ” founder BRCA1 mutation accounted for up to 20% distant metastases. The newest generation device of early-onset breast cancer in Ashkenazi Jewish removes normal blood cells, leaving behind viable women (5). cancer cells for molecular analysis (8). Those cancer “ Testing for BRCA mutations was quite contro- cells from the blood can be cultured and tested for ’ versial back in 1996, since it wasn t clear what to do drug-sensitivity patterns (9). Importantly, they can be with that knowledge,” explains Haber. “Now, BRCA analyzed at the single-cell level for DNA, RNA, and mutation carriers are extensively screened, and if they protein (10). “We are now trying to push the technology do develop cancer, their specific targeted treatments using advanced sequencing approaches to see if we are based on the fact that they have a BRCA muta- can diagnose early, potentially curable, invasive can- tion.” Following up on this laboratory work, Haber cers in individuals who are at high risk, either because of helped start genetic counseling programs in breast, genetic or environmental factors,” says Haber. colon, melanoma, kidney, and endocrine cancers For his Inaugural Article (1), Haber examined how at MGH.

Load more